Daily Cardiology Research Analysis
Analyzed 195 papers and selected 3 impactful papers.
Summary
Three advances stand out today: (1) genetic evidence that lowering lipoprotein(a) and interleukin-6 signaling reduces cardiovascular risk additively, informing combination therapy; (2) a proteomic risk score improves prediction of incident hypertension beyond clinical and genetic factors; and (3) an instrumental-variable nationwide analysis finds no clinical benefit of routine PCI before TAVR, favoring selective revascularization.
Research Themes
- Targeting residual cardiovascular risk via Lp(a) and inflammation
- Proteomics and AI-enabled risk stratification in hypertension
- Revascularization strategy optimization prior to TAVR
Selected Articles
1. Genetic variants lowering lipoprotein(a) and downregulating interleukin-6 signalling are additively associated with a decreased risk of cardiovascular disease.
In >400,000 UK Biobank participants, genetically lower Lp(a) and reduced IL-6 signaling each associated with lower risks of major cardiovascular outcomes. Importantly, the combined genetic exposures produced an additive reduction in coronary risk, corroborated by observational analyses stratified by circulating IL-6 and Lp(a) levels.
Impact: This provides robust causal and corroborative evidence that dual-targeting Lp(a) and inflammation may address residual cardiovascular risk beyond current therapies.
Clinical Implications: Supports development and testing of combination strategies (e.g., Lp(a)-lowering agents plus IL-6 pathway inhibitors) to reduce residual risk, independent of each pathway alone.
Key Findings
- Lower genetically predicted Lp(a) reduced CHD risk (OR 0.68 per 50 mg/dL lower), and also IS, PAD, HF, and AA risks.
- Lower IL-6 signaling reduced CHD (OR 0.67 per 0.5 log CRP reduction), AF (OR 0.72), and AA (OR 0.43).
- Combined lower Lp(a) and IL-6 signaling additively reduced CHD risk (OR 0.25 vs. either alone).
- Observational analyses: Lp(a) <50 mg/dL and IL-6 below median independently and additively lowered CHD risk.
Methodological Strengths
- Large-scale Mendelian randomization in 408,687 participants with observational validation
- Consistent findings across multiple CVD endpoints and interaction assessments
Limitations
- Primarily European ancestry may limit generalizability
- MR susceptible to pleiotropy; IL-6 signaling proxies may not fully recapitulate pharmacologic inhibition
Future Directions: Randomized trials testing combined Lp(a)-lowering and IL-6 pathway inhibitors to quantify additive clinical benefit and safety across diverse populations.
AIMS: Observational studies have yielded conflicting evidence regarding the interdependence between lipoprotein(a) [Lp(a)]-related cardiovascular risk and systemic inflammation. It remains unclear whether combined targeting of Lp(a) and inflammation provides additive cardiovascular benefits. This study aimed to investigate the associations between genetically predicted lower Lp(a) and cardiovascular disease (CVD) across interleukin-6 (IL-6) signalling levels and the combined effects of lower Lp(a) and IL-6 signalling activity on CVD risk. METHODS AND RESULTS: This study included UK Biobank participants of European ancestry. Genetic scores for LPA and IL-6 receptor (IL6R)-mediated signalling were calculated to mimic the effects of therapies targeting Lp(a) and IL-6 signalling, respectively. We investigated the associations of separate and combined exposure to lower Lp(a) and IL-6 signalling with coronary heart disease (CHD), ischaemic stroke (IS), heart failure (HF), atrial fibrillation (AF), peripheral artery disease (PAD), and aortic aneurysm (AA), using Mendelian randomization analyses and validating the findings in observational analyses. This study included 408 687 UK Biobank individuals (mean age, 57 years; 54% women). Genetically predicted lower Lp(a) was associated with reduced risks of CHD [odds ratio (OR) per 50 mg/dL reduction in Lp(a) levels, 0.68; 95% confidence interval (CI), 0.65-0.71], IS (0.89, 0.80-0.98), PAD (0.68, 0.62-0.76), HF (0.82, 0.77-0.88), and AA (0.71, 0.61-0.82). Genetically lower IL-6 signalling was associated with lower risks of CHD (OR per 0.5 log[mg/L] reduction in log-transformed C-reactive protein levels, 0.67; 95% CI, 0.55-0.82), AF (0.72, 0.55-0.94), and AA (0.43, 0.23-0.83). The genetic association between Lp(a) and CVD was consistent among individuals with different IL-6 signalling activity (P for difference > 0.05). Combined exposure to genetically predicted lower Lp(a) and IL-6 signalling was associated with an additive decrease in CHD risk (lower Lp(a): 0.67, 0.63-0.71; lower IL-6 signalling: 0.61, 0.46-0.80; combined: 0.25, 0.21-0.30; P for interaction = 0.144). In observational analyses, IL-6 levels below the median and Lp(a) concentrations below 50 mg/dL were also independently and additively associated with lower CHD risk (Lp(a) < 50 mg/dL: hazard ratio, 0.82; 95% CI, 0.72-0.93; IL-6 < median: 0.79, 0.65-0.96; combined: 0.65, 0.56-0.74; P for interaction = 0.102). CONCLUSION: Lower Lp(a) levels were associated with a reduced risk of CVD, independent of IL-6 signalling activity. Combined exposure to genetic variants lowering Lp(a) and downregulating IL-6 signalling was associated with an additive reduction in cardiovascular risk. These findings indicate that concurrent Lp(a)-lowering and anti-inflammatory therapies may reduce residual cardiovascular risk through additive effects. Combined intervention for both lipoprotein(a) [Lp(a)] and IL-6 signalling may reduce cardiovascular risk more than either monotherapy.A reduction in cardiovascular risk was observed with genetically lower Lp(a) levels, irrespective of IL-6 signalling activity.The combined effect of genetic variants that lower Lp(a) and downregulate IL-6 signalling led to an additive reduction in cardiovascular risk.
2. Proteomic Risk Score for Prediction of Incident Hypertension.
A proteomic risk score trained in UK Biobank improved prediction of incident hypertension beyond demographics, clinical risk factors, and a polygenic risk score, and replicated in an external cohort. Each 1-SD increase in ProtRS was associated with a 68% higher hazard of hypertension.
Impact: Demonstrates translational value of plasma proteomics for individualized hypertension risk stratification, potentially enabling earlier, targeted prevention.
Clinical Implications: Proteomic scoring could identify high-risk individuals for intensified lifestyle or pharmacologic prevention, complementing traditional and genetic risk assessment.
Key Findings
- In the test set, a 1-SD higher ProtRS associated with incident hypertension (HR 1.68; 95% CI 1.59–1.78) after multivariable adjustment.
- ProtRS improved prediction beyond demographics, clinical risk factors, and a polygenic risk score.
- External replication in the Asklepios study supported generalizability.
Methodological Strengths
- Derivation/test split with penalized Cox modeling and sequential risk factor adjustment
- External cohort replication supports robustness and transportability
Limitations
- Observational design limits causal inference on proteins and hypertension
- Incremental utility, thresholds, and clinical pathways for implementation require prospective testing
Future Directions: Prospective intervention studies using ProtRS to guide preventive strategies; mechanistic work to link key proteins to hypertension pathobiology.
BACKGROUND: Proteomic signatures may enhance the prediction of cardiometabolic diseases for targeted prevention. We evaluated whether a proteomic risk score (ProtRS) improves the prediction of incident hypertension. METHODS: Within the UK Biobank Proteomics data set, participants at risk for incident hypertension were randomly split into derivation (n=25 158) and test (n=10 781) sets. A ProtRS was trained in the derivation cohort using least absolute shrinkage and selection operator penalized Cox regression and evaluated in the test set with sequential adjustment for demographics, clinical risk factors, and a polygenic risk score (PRS). External replication was performed in the Asklepios study (n=793). RESULTS: In UK Biobank Proteomics (2312 events), each 1-SD higher ProtRS was associated with incident hypertension after covariate adjustment (hazard ratio, 1.68 [95% CI, 1.59-1.78]; CONCLUSIONS: A ProtRS improves prediction of incident hypertension beyond demographics, clinical, and genetic information in UK Biobank Proteomics, with supportive external replication. Proteomic information may enhance individualized hypertension risk stratification and provide biologic insights into disease development.
3. PCI Versus Conservative Management Before TAVR in Patients With Significant Coronary Artery Disease: A Nationwide Instrumental Variable Analysis.
Using an instrumental-variable approach in a nationwide cohort, routine PCI before TAVR did not improve the composite of death, MI, and urgent revascularization. PCI reduced nonurgent revascularization but increased bleeding, supporting selective rather than routine pre-TAVR PCI.
Impact: Addresses a common, practice-defining question with quasi-experimental methods and nationwide data, guiding coronary strategy in TAVR candidates.
Clinical Implications: Routine pre-TAVR PCI should not be assumed beneficial; consider ischemic burden, bleeding risk, and future coronary access to individualize revascularization strategy.
Key Findings
- No improvement in the primary composite (death, MI, urgent revascularization) with pre-TAVR PCI (IV-adjusted HR 0.98; 95% CI 0.85–1.14).
- Pre-TAVR PCI reduced nonurgent revascularization but increased bleeding events.
- Supports selective, not routine, pre-TAVR revascularization.
Methodological Strengths
- Nationwide registry with instrumental-variable analysis to mitigate unmeasured confounding
- Comprehensive assessment of ischemic and bleeding outcomes
Limitations
- Observational design; IV assumptions (relevance, exclusion restriction) cannot be fully verified
- Lesion-level ischemia and anatomical complexity details may be limited
Future Directions: Prospective randomized or pragmatic trials in defined ischemia strata; decision tools integrating bleeding risk and post-TAVR coronary access feasibility.
BACKGROUND: The optimal management of coronary artery disease in patients undergoing transcatheter aortic valve replacement (TAVR) remains unclear, and evidence supporting routine percutaneous coronary intervention (PCI) beforehand is limited. This study aimed to evaluate whether PCI before TAVR provides clinical benefit compared with conservative management in patients with significant coronary artery disease, using nationwide Swedish registry data. METHODS: This observational study included 2578 Swedish patients with significant coronary artery disease (≥50% angiographic stenosis or physiologically significant lesions) who underwent TAVR between 2008 and 2023. 1182 underwent PCI before TAVR, and 1396 were managed conservatively. The primary outcome was a composite of all-cause mortality, myocardial infarction, and urgent revascularization. Secondary outcomes included the individual components, cardiovascular mortality, any revascularization, stroke, and bleeding. The primary analysis used an instrumental variable approach based on each region's quarterly PCI treatment preference to account for confounding. RESULTS: PCI was not associated with a significant difference in the primary composite outcome (instrumental variable-adjusted hazard ratio, 0.98 [95% CI, 0.85-1.14]; CONCLUSIONS: In this nationwide cohort, PCI before TAVR did not improve survival or reduce urgent revascularization but did reduce nonurgent revascularization at the cost of increased bleeding. Decisions should be individualized, balancing ischemic and bleeding risks and considering anticipated coronary access after TAVR.